1-alkoxy-9-keto-prostenoic acid derivatives

ABSTRACT

This disclosure describes certain 11-alkoxy-9-keto-(or hydroxy)prostenoic acid derivatives useful as antimicrobial agents, hypotensive agents, anti-ulcer agents, or as intermediates.

United States Patent Floyd, Jr. et al.

[ 1 Apr. 8, 1975 l-ALKOXY-9-KETO-PROSTENOIC ACID DERIVATIVES Inventors: Middleton Brawner Floyd, Jr.,

Suffern, N.Y.; Martin Joseph Weiss,

Oradell, NJ.

Assignee: American Cyanamid Company,

Stamford, Conn.

Filed: May 11, 1973 Appl. No.: 359,391

U.S. CI 260/514 D; 260/345.8; 260/395'. 260/410.9 R; 260/413; 260/468 .1; 260/468 K; 260/468 D; 260/473; 260/501.1; 260/501.17; 260/514 K; 260/514 1,424/305;

424/317 Int. Cl. C07c 61/36; C070 69/74 Field of Search 260/468 D, 514 D, 395

OTHER PUBLICATIONS Ryhage et al., Biochemical & Biophysical Research Communication, 19, 279 (1965).

Primary ExaminerRobert Gerstl Attorney, Agent, or Firm-Edward A. Conroy, Jr.

[57] ABSTRACT This disclosure describes certain 1 1-a1koxy-9-keto-(or hydroxy)-prostenoic acid derivatives useful as antimicrobial agents, hypotensive agents. anti-ulcer agents. or as intermediates.

13 Claims, No Drawings l-ALKOXY-9-KETO-PROSTENOIC ACID DERIVATIVES BRIEF SUMMARY OF THE INVENTION This invention relates to novel 1 l-alkoxy substituted prostanoic acids and derivatives as well as to intermediates and methods for their preparation. The novel compounds of this invention may be represented by the following general formula:

wherein R, is lower alkoxy, m-hydroxy-substituted lower alkoxy, or w-tetrahydropyranyloxy-substituted lower alkoxy; R is hydrogen, lower alkyl, or triphenylmethyl; R is a straight chain alkyl group having from 2 to 10 carbon atoms, a straight chain alkyl group having from 2 to 10 carbon atoms and substituted with one or two lower alkyl groups, a straight chain alkenyl methyl group having from 3 to 10 carbon atoms, a straight chain alkenyl methyl group having from 3 to 10 carbon atoms and substituted with one or two lower alkyl groups, a cycloalkyl group having from 4 to 9 carbon atoms, lower alkyl substituted cycloalkyl group having from 5 to carbon atoms, a cycloalkylsubstituted lower alkyl group having from 6 to 12 carbon atoms and in which the cycloalkyl group is optionally substituted with a lower alkyl group, a cycloalkenyl group having from 5 to 9 carbon atoms, a lower alkyl substituted cycloalkenyl group having 6 to 10 carbon atoms, a cycloalkenyl substituted lower alkyl group having from 6 to 12 carbon atoms and in which are cycloalkenyl group is optionally substituted with a lower alkyl group, admantyl, or an adamantyl substituted lower alkyl group; R, is hydroxy, an alkoxy group having from 1 to 12 carbon atoms, or tetrahydropyranyloxy; R is hydrogen or a lower alkyl group having up to 3 carbon atoms; Y is a divalent radical se lected from the group consisting of those of the formulae:

0 HO H H OH ll C O and C and Z is a divalent radical selected from the group consisting of those of the formulae:

wherein n is an integer from 3 to 8, inclusive, p is an integer from 2 to 6 inclusive, R is an alkyl group having up to 3 carbon atoms, and R is an alkyl group having up to 3 carbon atoms, a fluorine atom or a phenyl group; and the moiety -C C is ethylene or transvinylene; with the proviso that when R is a lower alkyl group then R is hydrogen; and all optical isomers thereof.

Also embraced within the scope of the present invention are the non-toxic, pharmaceutically acceptable salts of the novel compounds of the present invention when R, is hydroxy. The cations comprised in these salts include, for example, the non-toxic metal cations such as the sodium ion, potassium ion, calcium ion, and magnesium ion as well as the organic amine cations such as the tri(lower alkyl)amine cations (e.g., triethylamine, triethanolamine, procaine, and the like).

The novel compounds of the present invention are obtainable as yellow oils having characteristic absorption spectra. They are relatively insoluble in water but are relatively soluble in common organic solvents such as ethanol, ethyl acetate, dimethylformamide, and the like. The cationic salts ofthe compounds when R, is hydroxy are, in general, white to yellow crystalline solids having characteristic melting points and absorption spectra. They are relatively soluble in water, methanol, and ethanol but are relatively insoluble in benzene, diethyl ether, and petroleum ether.

DETAILED DESCRIPTION OF THE INVENTION H em cr CH1 COOH l cm 0 1 c 10 ii CH CH CH CH 11 1 Z 2 3 rbcn, CH1 CH:

The hydrogen atoms attached to C-8 and C-12 are in trans-configuration. The natural prostaglandins represent only one of the possible optical isomers. The compounds of this invention include all possible optical isomers.

The novel compounds of the present invention may be readily prepared from certain 4-substituted cyclopentenone intermediates which may be represented by the following general formula:

wherein R, is lower alkoxy or m -tetrahydropyranyloxysubstituted lower alkoxy; R, is tetrahydropyranyloxy or an alkoxy group having from I to 12 carbon atoms; and Z is as hereinabove defined.

Certain of the 4-oxycylopentenone intermediates may be prepared from the corresponding 4- unsubstituted cyclopentenones (I) in accordance with the reaction scheme of Flowsheet A, wherein Z embraces all of Z, but not cis CH CI-I CI-I(CI-I- The requisite cyclopentenones are described in Belgium Pat. No. 786,215 (granted and laid open to inspection on Jan. 15, 1973) or can be obtained by analogous procedures to those described in the aforesaid patent.

In Flowsheet A which follows, Z, R and R are as hereinabove defined; R is a lower alkyl group, R", is hydroxy or an alkoxy group having from one to 12 carbon atoms, and m is an integer from two to five inclustve.

FLOWSHEET A unsubstituted cyclopentenones (I) is accomplished by first halogenating the 4-position with an allylic halogenating reagent, preferably N-bromosuccinimide. The resulting 4-bromocyclopentenones (II) is then solvolyzed for the introduction of the oxy function. This step is preferably carried out in the presence of a silver salt to facilitate the displacement of the halide ion. The particular 4-oxy derivative that is formed is determined by the nature of the solvent system. Treatment of the 4- bromocyclopentenone with silver fluoroborate in water-acetone (for solubility) provides the 4- hydroxycyclopentenone. When the solvent system is water-tetrahydrofuran, in addition to the 4-hydroxy derivative there is also obtained the 4-hydroxybutyloxy derivative (III), formed by solvolysis with tetrahydrofuran. When the solvent is only tetrahydrofuran then only the latter compound is formed. Substitution of tetrahydrofuran with alcohols, e.g., methanol, ethanol, isopropanol, butanol and the like, provides the 4- alkoxycyclopentenones (IV). With ethylene glycol or propylene glycol etc. the corresponding 4-(wsubstituted hydroxy alkoxy)-cyclopentenone (V) is obtained. In the latter three procedures it is preferably to example, sym-collidine.

In general these procedures are operable with either the free carboxylic acid or alkyl carboxylate, as desired. A particular alkyl carboxylate not provided by formula (I) can be obtained by hydrolysis to the acid and esterification in the usual way, for example with the appropriate alcohol, or for a t-butyl ester with isobutylene. However, for the subsequent alanate conjugate addition process it is necessary to utilize a cyclopentenone wherein the carboxylic acid as well as all free hydroxy] groups are blocked. A particularly useful blocking group for both functions is the tetrahydropyranyl group since the group can easily be cleaved with weak acid under conditions which do not disrupt the subsequently-prepared, relatively-unstable ll-oxy- 9-keto system (,B-oxy-ketone). Thus, it is not possible to effect a satisfactory chemical hydrolysis of an alkyl ester or of an O-alkanoyl group in an ll-oxy-9-keto prostanoic acid derivative under conditions to which this system is stable (enzymatic hydrolysis is possible). Of course these stability considerations do not apply in the F (9-hydroxy) series.

The 9-keto-l3-trans-prostenoic acids and esters of this invention nay be prepared via the novel conjugate addition processed outlined in the Flowsheet B which follows. In Flowhseet B, R R',, R',, R,, and Z are as defined hereinabove; R,. is a lower alkyl group (each of three R, radicals bonded to a aluminum does not necessarily have to be the same), R' is lower alkyl or triphenylmethyl, R is hydrogen or lower alkyl and R" is lower alkoxy or w-hydroxy-substituted lower alkoxy.

FLOWSHEE'I B .AICI; CHECH Rz In (VII) (VIII) 0 I II (i l-R3 e H R3 trans I & trans I l 61 H I I (IX) (X) 0 R: O H H (DH-R H t dlH-R;

trans rans I H I H (XI) (XII) O H RQOHO LiCECH R -H-CECH (XIII) (XIV) l (X B HCECH (XVI) O R: O RIQ H H-R H HR3 trans J: (RghAl (g trans l I at I Li H Rr-AlRs H l a; Rs L1 (XVII) (XVIII) FLOWSHEET B-Continued O (XVIIIa) In accordance with the reaction scheme of Flowsheet B, acetylene (VII) is treated with an appropriate acid chloride (VIII) in the presence of aluminum trichloride to provide the l-chloro-3-keto-trans-l-alkene (IX). Interchange with sodium iodide, preferably in a ketone solvent such as acetone, provides the corresponding trans-vinyl iodide (X). Reduction of the keto function in (X) with sodium borohydride furnishes the alcohol (XII), which is then blocked with the triphenylmethyl group or a triphenylmethyl group substitued with one or two methoxy groups or an O-lower alkyl group is introduced. Blocking the hdyroxy function can also be accomplished with a trialkylsilyl group.

The blocked trans-vinyl iodide can also be obtained by treatment of the appropriate aldehyde (XIII) with lithium acetylide (XIV) in the usual manner, blocking the product 3-hydroxy-l-alkyne (XV) and then, in one operation, treating the resulting (XVI) successively with disiamylborane,trimethylamine N-oxide, and iodine and auqeous sodium hydroxide. to give (XI). This latter procedure is preferred when R is adamatyl, contains a center of unsaturation, a cyclopropyl ring or other relatively sensitive feature.

The blocked vinyl iodide (XI) is then submitted to metal interchange with an alkyl lithium, e.g. n-butyl lithium, at very low temperatures, e.g. 78c., which provides the vinyl lithium derivative (XVII), the transconfiguration of the double bond being retained. After 1 to 4 hours, addition of a trialkyl aluminum [(Rg)3Al], preferably trimethyl aluminum, to the solution of the lithio derivative (XVII) furnishes the lithio alanate intermediate (XVIII), also with retention of the transconfiguration of the double bond. The cycloalkenone (XVIII), dissolved in ether or other non-prototropic solvent, is then added to the alanate solution. The resulting solution is allowed to warm to room temperature and is kept for about 6 to 18 hours at ambient temperatures. Potential hydroxy or carboxylic acid groups in cycloalkenone (XVIIla) are blocked as ethers or esters, preferably, with tetrahydropyranyl and/or trialkylsilyl groups. Interchange of alanate (XVIII) with cycloalkenone (XVIIIa) results in the transfer of the trans-l-alkenyl ligand in (XVIII) with retention of the trans-configuration in a 1,4-conjugate manner to the cycloalkneone (XVIIIa) furnishing, after quenching the reaction solution, the 1,4-conjugate addition product (XIX). It is important to note too that the transalkenyl ligand from (XVIII) adds trans to the 4- substituent in (XVIIIa). In (XIX) we are however not certain of the relative configuration of the side chains to each other. The situation is indicated in structure (XIX) by the M bond between the ring and the 0 l ZC-R4 chain and is indicated in the nomenclature of the compounds involved by the designation 8E. In any event deblocking to (XX) with acid, e.g. treatment with acetic acid: tetrahydrofuran: water in the ratio of 3:12! at 35-45C. for from 3 to 48 hours, results in the transrelationship between the chains. This procedure results in de-O-tritylation as well as hydrolysis of tetrahydropyranyl and trialkylsilyl groups.'Alkyl esters are not cleaved by this procedure, however these esters can be hydrolized by enzymatic or microbiological techniques known to the art.

In order to ensure a trans-relationship in (XIX) these products can be submitted to conditions known in the literature to equilibrate the 8-iso PGE, to a mixture containing about of the trans product. These conditions involve treatment with potassium acetate in aqueous methanol for 96 hours at room temperature.

An alternative route, also involving conjugate addition of an alanate to a cycloalkenone, is outlined in Flowsheet C, which follows. In Flowsheet C R R,,, Z, R,, R and R, are as hereinabove defined.

FLOWSHEET C-Continued OH a R"1 CH CH-R trans OH (XXVII) In accordance with the reaction scheme of Flowsheet C, the triphenylmethoxy substituted l-alkyne (XXI), prepared by O-triphenylmethylation of the corresponding l-alkyne-3-ol (XV, Flowsheet B), is treated with diisobutylaluminum hydride (XXII), which provides the alane (XXIII) containing the trans-double bond and is carried out in an inert solvent such as benzene, toluene, and the like at temperatures in the range of 4060C. for several hours. It can also be carried out in a solvent such as tetrahydrofuran, usually in an approximate 2:1 mixture with benzene or hexane; in which case the reaction requires somewhat more vigorous conditions, usually heating at about 70C75C. for about eighteen hours. The subsequent reaction with methyl or n-butyl lithium (R -Li) is preferably carried out in a mixture of the above solvents with an ethertype solvent such as diethyl ether, dibutyl ether, tetrahydrofuran and the like. This reaction is rapid and is preferably carried out at OCl0C. with cooling. The conjugate 1,4-addition of the resulting alanate salt (XXV) to the 4-oxy-cyclopent-2 -en-l-one (XXIV) is preferably carried out at ambient temperatures for a period of 12 to 24 hours. This reaction is also best carried out in an ether-type solvent such as diethyl ether,

dibutyl ether, tetrahydofuran, and the like. The intermediate alanate-enolate adduct is then carefully hydrolzed in situ, with dilute hydrochloric acid with cooling, and the product (XXVI) is isolated in the usual manner, well known in the art. Removal of tetrahydropryanyl blocking groups and of the triphenylmethyl blocking group can then be accomplished by treating with weak acid. A preferred procedure involves heating at 45C. for 3.5 hours in a solvent system consisting of acetic acidztetrahydrofuranzwater in the proportion of 4:2:1. If (XXVI) is a tetrahydropyranyl ester, there is then obtained the prostenoic acid (XXVII,R" =hydroxy).

The 9-keto derivatives (XXVIII) of this invention can be converted to the corresponding 9-hydroxy derivatives. If this conversion is effected with sodium borohydride, the product is a mixture of 9aand 9B- hydroxy derivatives (XXIX) and (XXX) as set forth in the following reaction scheme:

0 R2 (XXVIII) In Flowsheet D R,, R R R R Z and C, -C are as hereinabove defined. When the reaction is carried out with lithium perhydro-9b-boraphenylyl hydride [I-I. C. Brown and W. C. Dickason, Journ. Amer. Chem. Soc., 92, 709 (1970)] the product is at least predominantly the 9oz-hydroxy derivative (XXIX), wherein the 9-hydroxy group is cis to the side-chain attached to C and to the ll-oxy function.

Those compounds of this invention embodying the CH CH lingage at C C may be prepared from the corresponding A derivatives, obtained via the alanate process, by catalytic reduction, preferably at low pressure with a noble metal catalyst in an inert solvent at ambient temperatures.

In accordance with accepted convention, an a-sub' stituent at the 8-, 9-, l lor l2-positions is behind the plane of the paper whereas a B-substituent at these positions is in front of the plane of paper. This is usually represented by a a bond for an a-substituent, a

bond for a B-substituent, and a bond where both areindicated. Thus, the 9-hydroxy derivatives may be variously represented as follows:

The novel compounds of the present invention have utility as hypotensive agents, anti-ulcer agents, agents for the treatment of gastric hypersecretion and gastric crosion, bronchodilators, antimicrobial agents, anticonvulsants, abortifacients, agents for the induction of labor, agents for the induction of menses, fertilitycontrolling agents, central Nervous system regulatory agents, analgesic agents, salt and water-retention regulatory agents, diuretics, fat metabolic regulatory agents, serum-cholesterol lowering agents, antiinflammatory agents and as agents for the inhibition of platelet aggregation, and for the treatment of periodontal disease, glucoma, uveitis, sickle cell anemia and psoriasis. Certain of the novel commpounds of this invention possess utility as intermediates for the prepara tion of other of the novel compounds of this invention.

The compounds of this invention also provide protection against the ulcerogenic properties of certain nonsteroidal anti-inflammatory agents, e.g., indomethacin, aspirin, and phenylbutazone.

The novel compounds of the present invention are useful as hypotensive agents and their hypotensive activity was demonstrated in the following test procedure. This procedure is a modification of the technique described by Pike et al., Prostaglandins, Nobel Symposium 2, Stockholm, June, 1966; p. 165.

Male Wistar strain rats (Royal Hart Farms) averaging approximately 250 grams in weight were fastened to rat boards in a supine position by means of canvas vests and limb ties. The femoral area was infiltrated subcutaneously with lidocaine and the iliac artery and vein were exposed and cannulated. Arterial blood pressure (systolic/diastolic) was recorded using a Statham P Db pressure, the animals were anethetized before use with pentobarbital, 30 mg./kg. of body weight intravenously, and also were given hexamethoxium bitartrate, 2 mg./kg. of body weight intravenously. The test compounds were prepared by ultrasonic dispersion in a saline-Tween 8O vehicle. A constant intravenous dose volume of 0.5 ml. was administered and test doses ranged from 0.1 to 10.0 mg./kg. of body weight. Increasing or decreasing doses were selected depending on the dose response obtained. In Table I below are set forth doses at which at least a decrease of about mm. in diastolic blood pressure was observed for typical compounds of the present invention.

TABLE 1 Effective dose (mg/kg. of

- l 3-trans-pr0sten0ic acid 9-oxo-l la-methoxyl S-hydroxyl 5-methyll 3-trans-prostenoic acid 9-oxo-l la-methoxyl 5-hydroxyl6,16-dimethyl-l3-trans-prostenoic acid 9-oxo-l lamethoxyl S-hydroxy- -13-trans, l 7-cis-prostadienoic acid 9-oxo-3-oxa-l la-methoxyl 5-hydroxyl 6, l 6-dimethyll 3-trans- -prostenoic acid 9-oxo-l la-methoxyl S-hydroxy- -l5 methyll 7,1 8-cis-methanol B-trans-prostcnoic acid 9oxo-l la-methoxyl S-hydroxyl 5- -hydroxy- 16,19-trans-ethanol 3- -trans-prostenoic acid 9-oxo-l loz-( Z-hydroxyethoxy l 5- -hydroxyl 3-trans-prostenoic acid 9-oxo-l la-( 2-hydr0xyethoxy)- l Shydroxyl 6, l 6-dimethyll 3-trans- -prostenoic acid 9-oxo-l la Z-hydroxyethoxy l 5- -hydroxyl 3-truns, l 7-cis-prostadienoic acid This invention will be described in greater detail in conjunction with the following specific examples.

In the following examples, unless otherwise specified, the products obtained include all possible optical isomers.

EXAMPLE 1 Preparation of 2-(6-carboxy-6-fluorohexyl)cyclpent-2-en-1-one This cyclopentenone is prepared by the procedure described in Belgium Pat. No. 786,215 (Jan. 15, 1973) for the preparation of 2-(6-carboxyoctyl)cyclopent-Z- en-l-one by substituting diethyl fluoromalonate for diethyl ethylmalonate.

EXAMPLE 2 EXAMPLE 3 Preparation of 2-( 6-carboxyheptyl )cyclopent-Z-en- 1 -one This cyclopentenone is prepared by the procedure described in Belgium Pat. No. 786,215 (Jan. 15, 1973) for the preparation of 2-(6-carboxyheptyl)cyclopent-2- en-l-one by substituting diethyl methyl malonate for diethyl ethylmalonate.

EXAMPLE 4 Preparation of 2-(6-carbo-n-butoxyhexyl)cyclopent-2-en-1-one A solution of 50 g. of 2-(6-carboxyhexyl)cyclopent- 2-en-l-one Bagli et al., Tetrahedron Letters, No. 5, 465 (1966)] in 1400 ml. of n-butanol containing 2.7 g. of p-toluenesulfonic acid monohydrate is allowed to stand at room temperature in a stoppered flask for about 24 hours. The solution is taken to dryness. The residue is taken up in ether and the ethereal solution is washed several times with saline solution, dried with anhydrous magnesium sulfate, and taken to dryness to afford the subject butyl ester.

EXAMPLES 5-7 .Treatment of 2-(6-carboxyhexyl)cyclopent-Z-enl-one by the procedure of Example 4 with the appropriate alcohol affords the esters of the following table.

-l-one Table 2-Continued Starting bromo- Product 4-alkoxycyclo- 9), 3.01 g. (11 moles) of silver carbonate, and 40 ml. of t-butanol is heated at 70C. for 17 hours. The mixture is cooled and filtered. After evaporation of tg g fffg f g butanol the residue is treated with' aqueous sodium p p a chloride and extracted with 3:1 ether-hexane. The extract is washed with saturated sodium chloride solution, .en-l-one dried over magnesium sulfate, and concentrated. The 37 13 I ;P;2 Y- crude product is purified by chromatography on silica ,,,f 'i, y gel to give in order of elution: the subject compound as 38 I3 4-meth0 yfl an oil; )tmax. MeOH 219 mu (8860);-vmax. 1735 Pfj fvfgig (ester carbonyl group), 1725 ketone carbonyl group). 39 14 4-ethoxy-2-(3-carboxy and 1365 cm (tert.-butyl group); and 4-hydroxy-2- P fg g (6-carbethoxyhexyl)cyclopent-Z-en-l-one also as an 40 1S 4-methoxy-2-(8-car- Oil hoxyoctyl)cyclopentl5 EXAMPLE 63 -2-en-l-one 41 16 4-isopropoxy-2-( 8-carbethooxyoctyhcyclo Preparation of pent-. -en-l-onc 42 I7 4 (2 hydroxyethoxy) 2 (6lcarboxyhexyl)cyclopent 2 hoxyoctyl)cyclopent- -2- -lno 43 [g l, To a stirred solution of 19.1 g. of crude 4-bromo-2- m u m' (6-carboxyhexyl)cyclopent-2-en-one (Example 8) in 44 19 f ;3: 310ml. of ethylene glycol is added 15.6 g. (80 mmole) -5.5-dimet1;ylhexy of silver fluoborate during 2 minutes. The exothermic 4s reaction is controlled to give a temperature of 29C., thoxy-5.5-dimethylhexand after 1 minute the mixture is treated during 1 min- 46 a 3i ute with 8.6 g. (80 mmole) of 2,6-lutidine. The mixture g ,,g g is stirred at ambient temperature for 2 hours. diluted e og b with water, and filtered. The filtrate is diluted with sat- 47 ifig igigg ifi urated sodium chloride solution and extracted with pent-Z-cn-l-one ether. The extract is washed with half-saturated sodium 33 chloride solution containing a little hydrochloric acid pent-Z-en-l-one and saturated sodium chloride solutionfThe extract is 9 24 yg dried over magnesium sulfate and concentrated. ColpfmyncycIOPem-en' umn chromatography of the residue on silica gel gives 'Ol'lfi I 50 25 )ian oil, A max. MeOH 216 mu (8350); 11 max. 3340 me Opem' (hydroxyl groups), 1700 (carbonyl groups), and 1620 51 26 4-methoxy-2-(7-carboxycm (olefin group).

h1eptyl)cyclopent-2-en- EXAMPLES 64 85 -Ofl 5 2 27 4-methoxy-2-( 7-carbg g f zgg By the procedure described in Example 63, treat- 53 28 -gment with the appropr ate (1101 of the var ous 4- -P "y f y Y bromocyclopentenones listed in Table 3, whlch folpent-..-en- -one 54 32 4 methoxy z (6 carboxy lows, are converted to the corresponding 4 (w heptyl)-cyclopent-2- hydroxyalkyl)cyclopenteneones of the Table. -en-l-one 55 29 4-methoxy-2-(6-carbo- -n-butoxyhexyl)cyc1opent-2-en- 1 -one 56 30 4 -methoxy-2-(6-carbo- -rsoproopoxyhoerxg l)cyclopen -..-en- 57 31 l i l i TABLE 3 -necy oxy exy eye 0- Startin 4 b P d g romoro uct 4-(arhydroxy- 58 8 Excyclopentcnone alkoxy)cyclopent-2-eng ggg ample of Example -1-one 59 8 4-propoxy-2-(6-carboxy- 64 9 4 B h I 7 ydroxyethoxy- -(6- ggi -carbethoxyhexyl )cyclo- T I pent-Z-en-l-onc 8 (Hum 65 10 4-l3-hydroxyethoxy-2-( 6- g g g' Opem' -carbomethoxyhexyl )cyclopent-2-en-1-one 8 g' i 'fl 66 1 1 47hydroxypropoxy-Z- OXY exy )CYC ,0 -(4-carbethoxybutyl)- 1 cyclopent-Z-cnl-one 67 12 4-B-hydroxyethoxy-2-( 3- -carbethoxypropyl)cyclopent-2-cn-1onc EXAMPLE 62 68 13 4-l3-hydroxyethoxv-2-(4- -carboxybutyl )cyc lopent- Preparation of 65 X hex l C C10 CIlt-Z-Efl- 69 14 4-[3-hydroxyethoxy-2-(3- 4 tert butoxy 2 (6 carbetho y y y P flrhoxypmpyhcyclo l'one pent-Z-en-l-one 70 15 4-B-hydroxyethoxy-2-( 8- A stirred mixture of 6.35 g. (20 mmoles) of 4bromo- 2-( carbethoxyhexyl )cyclopent-Z-en- 1 -one (Example -carboxyoctyl )cyclopent-2-cn- 1 -one 19 (6tetrahydropyranylcarboxyhexyl)-cyclopent-2-enl-one with dihydropyran and p-toluenesulfonic acid monohydrate in methylene chloride.

EXAMPLE 127 Preparation of 3-triphenylmethoxy-l-octyne A mixture of 1.26 g. (10.0 mmoles) of 1-octyn-3-o1, 4.85 g. 15.0 mmoles) of triphenylmethyl bromide, and 50 ml. of dry pyridine is heated at 95C. for 60 minutes with occasional swirling. The solution is cooled, treated with water, and extracted with ether. The extract is washed successively with water and saturated sodium chloride, dried over magnesium sulfate, and concentrated. The crude product is purified by chromatography on Florisil and recrystallization from petroleum ether to give white crystals, m.p. 6566C. A max. (KBr) 3280 (acetylenic hydrogen), 1605, 1030, and 702 cm (triphenylmethoxy group).

EXAMPLE 128 Preparation of liodo-3-triphenylmethoxy-transl octene To a mixture of 0.650 g. (16.91 mmole) of sodium borohydride and 3.17 g. (45.2 mmoles) of 2-methy1-2- butene in 40 ml. of diglyme cooled to 5C. under an inert atmosphere is added over 15 minutes 3.24 g. (22.6 mmoles) of boron trifluoride etherate and the resulting mixture is stirred at C. for 2 hours. To this mixture is then added over minutes 8.32 g. (22.6 mmoles) of 3-triphenylmethoxy-l-octyne (Example 127) in ml. diglyme, the cooling bath is removed, and the mixture is stirred at ambient temperature for 1.5 hours. The mixture is cooled to 0C. and 6.0 g. of finely divided anhydrous trimethylamine oxide is added over 10 minutes. The cooling bath is removed and the mixture is stirred at ambient temperatures for 0.5 hour. The mixture is then poured into 200 ml. of sodium hydrooxide solution, a solution of 16 g. (63 mmoles) of iodine in 20 ml. of tetrahydrofuran is added immediately, and the resulting mixture is stirred for 0.5 hour. The organic phase is separated and the aqueous phase is washed with ether. The combined organic phase and washings are decolorized with 5% sodium thiosulfate solution. washed with saturated brine, dried (Na SO and evaporated. The residue is dry-columned chromatographed upon alumina using hexane is eluent and the title compound is isolated as an oil.

EXAMPLES 129-138 In accordance with the method described in Example 127, the various 3hydroxyl-alkylenes listed in Table 6 below are converted to the corresponding 3-triphenylmethoxy-l-alkynes by treatment with triphenylmethyl bromide.

Table 6-Continued M. Bertrand. Bull. Soc. Chim. France. 461 (1956).

F. Bohlmann and D. Rutz, Chem. Ber., 90, 2265 (1957).

U.S. Pat. 3.452.105 (June 24, 1969); Chem. Abs" 71. 60678 (1969). "Sequin. Bull. Soc. Chim. France, 12, 948 (1945).

" J. Fried ct al., .lour. Amer. Chem. Soc.. 94, 4342 (1972).

EXAMPLE 138A Preparation of 3-methoxy-1-octyne To an ice-cooled solution of 63 g. of 1-octyn-3-ol in 300 ml. of dimethoxyethane is added under an inert atmosphere 312 ml. of 1.6 M n-butyllithium in hexane dropwise over 1 hour. To the mixture is then added 145 g. of methyl iodide and the resulting mixture is stirred at ambient temperatures for 24 hours and then heated to 60C. for 1 hour. The mixture is cooled and poured into cold dilute hydrochloric acid. The organic phase is separated, washed with water and saturated brine, dried (Na SO and evaporated to an oil, dried (Na. S0 and evaporated to an oil. Fractional distillation of the oil in vacuo yields the product as a colorless oil.

EXAMPLES 139-148 Treatment of the l-alkynes listed in Table 7 below with disiamylborane (prepared in situ from 2-methyl-2- butene, sodium borohydride and boron trifluoride), trimethylamine oxide, iodine and aqueous sodium hydroxide by the procedure described in Example 128 furnishes the product 3-tr1phenylmethoxy-1rodotrans-l-alkenes of the Table.

Table 7 Ex- Starting l-alkyne Product l-iodo-transample of Example l-alkene 139 129 1-iodo-3-triphenylmethoxy-trans-heptene 140 130 l-iodo-3-triphenylmeth oxy-trans l hexene 141 131 l-iodo-3-triphenylmethoxy-trans-l-pentene 142 132 l-iodo-3-triphenylmethoxy-transl nonene 143 133 l-iodo-3-triphenylmethoxy-trans- 1 decene 144 134 l-iodo-3-triphenylmethoxy-4-ethyl-trans-1- octene 145 135 1-iodo-3-triphenylmethoxy-4-methyl-transl heptene 146 136 1 iodo-3-triphenylmethoxy-7-methyl-trans- 1,6-octadiene 147 137 l-iodo-3-triphenylmethoxy-5,9-dimethyl-transl ,9-decadiene 148 138 l-iodo-3-triphenylmethoxy-trans-l ,cis5 octadiene 148A 138A 1-iodo-3-methoxy-transl-octene EXAMPLE 149 Preparation of 4,4-dimethyll -octyn-3-ol EXAMPLE I53 Preparation of 5,5-dimethyl-1-octyn-3-ol Treatment of 20.2 g. (0.220 mole) of lithium acety- To a solution of 20.2 g. (0.220 mole) of lithium acelide-ethylenediame complex in 100 ml. of dimethylsulftylide-ethylenediamine complex in 100 ml. of dry dimethylsulfoxide is added 25.6 g. (0.200 mole) of 2,2-dimethyl1-hexanal, prepared according to the procedure of G. Stork and S. R. Dowd, J. Amer. Chem. 1

$00., 85, 2178 (1963), in 25 ml. of dimethylsulfoxide at a rate to maintain a temperature of 25C. (cooling). The mixture is then maintained at 25C. for 2 hours and is poured onto ice and excess hydrochloric acid. The mixture is extracted with ether and the organic phase is washed with water and saturated brine, dried (Na S0 and evaporated to an oil. Distillation in vacuo yields the product as a colorless oil.

EXAMPLE 150 Preparation of 4,4-dimethyl-3tetrahydropyranyloxy- 1 -octyne EXAMPLE 151 Preparation of 4,4-dimethyl-l-iodo-trans-l-octen-3-ol To 233 ml. of a 0.43N solution of disiamylborane in diglyme cooled to 0C. under an inert atmosphere is added 23.8 g. (0.100 mole) 4,4-dimethyl-3-tetrahydropyranyloxy-l-octyne (Example 150). The mixture is allowed to come to room temperature and is stirred at ambient temperature for 3 hours. The solution is cooled to 0C. and 22.5 g. (0.30 mole) of triethylamine oxide is added portionwise such that the temperature is maintained at 05C. The mixture is stirred at 0C. for 1 hour and is then poured into 150 ml. of l N sodium hydroxide followed immediately by a solution of 25.4 g. (0.100 mole) of iodine in 60 ml. of tetrahydrofuran. The mixture is stirred at ambient temperatures for 0.5 hour and poured into 500 ml. of water. The mixture is decolorized by addition of sodium thiosulfate and is extracted into ether. The organic phase is washed with water and the solvent is removed in vacuo. The residue is stirred at room temperature for hours with 900 ml. 3:111 tetrahydrofuran-acetic acid-water. The solution is evaporated in vacuo and the residue is chromatographed on silica gel in benzene using l020% ethylacetate in benzene.

EXAMPLE 152 Preparation of 4,4-dimethyl-1iodo-3-triphenylmethoxy-trans-1- octene gives the title compound.

oxide with 25.6 g. (0.200 mole) of 3,3-dimethylhexanol [prepared according to the procedure of A. W. Burgstahler, J. Amer. Chem. Soc., 82, 4681 (1960)] and dis- 0 tillation of the product, all as described in Example 149 yields the title compound.

EXAMPLE 155 Preparation of 5,5-dimethyl-l-iodo-trans-l-octen-3-ol Treatment of 23.8 g. (0.100 mole) of5,5-dimethyl-3- tetrahydropyranyloxy-l-octyne (Example 154) successively with 233 mg. of 0.43 M disiamylborane in diglyme, 22.5 g. of trimethylamine oxide, 150 ml. of l N sodium hydroxide, 25.4 g. of iodine, and 900 ml. of

3:1:1 tetrahydrofuran-acetic acid-water as described in Example 151 gives the title compound.

EXAMPLE 156 Preparation of 5 ,S-dimethyll -iodo-3-triphenylmethoxy-transl octene Treatment of 6.0 g. of 5.5-dimethyl-l-iodo-trans-locten-3-ol (Example with 6.9 g. of triphenylmethyl bromide in 30 ml. of pryridine and purification on Florisil all as described in Example 127 gives the title compound.

EXAMPLE 157 Preparation of 1,l-dimethoxy-cis-3,4-methanohexane (cisl -ethyl-2-( 2,2-dimethoxyethyl )-cyclopropane) To an ethereal suspension of zinc-silver couple, prepared according to the procedure of]. M. Danis, C. Girand, and J. M. Conia, Synthesis, 1972, 549, from 0.400 g. of silver acetate, 400 ml. of acetic acid, 68 g. of granular zinc, silver wool, and 600 ml. of ether, is added dropwise 136 g. of diiodomethane at a rate to maintain a gentle reflux. The mixture is then stirred at room temperature for 1 hour and and to it is then added 57.7 g. of l,l-dimethoxy-cis-3-hexene (M. Winter, Helvetic'a Chimica Acta, 46, 1792 (1963)) over a period of 20 minutes and the mixture is refluxed for 5 hours. The mixture is cooled to 0C., 600 ml. of ether is added followed by 50.5 g. of pyridine dropwise over a period of 1 hour. The resulting precipitate is filtered and washed with ether. The filtrate and washings are combined and evaporated and the residue is fractionally distilled at 12 torr. to yield the title compound as a colorless oil.

EXAMPLE 158 Preparation of cis-3,4-methano-l-hexanol To a vigorously stirred solution of 31.6 g. of 1,1- dimethoxy-cis-3,4-methano-hexane (Example 157), 75

mg. of hydroquinone, 6 g. of oxalic acid in 150 ml. of acetone heated at 45C. under an inert atmosphere is added 700 ml. of water over a period of 0.5 hour. The mixture is cooled and extracted well with ether. The organic phase is separated, washed with saturated sodium bocarbonate solution and saturated brine. dried (Na S and evaporated. The residue is distilled at 30 torr. to yield the title compound.

EXAMPLE 159 Preparation of cis-5,6-methano-1-octyn-3-ol To a solution of 15.2 g. (0.165 mole) of lithium acetylide-ethylenediamine complex in 100 ml. of dry dimethylsulfoxide is added 16.8 g. (0.150 mole) of cis-3,4-methano-l-hexanol (Example 158) in 25 ml. of dimethylsulfoxide at a rate to maintain a temperature of 25C. (cooling). The mixture is then maintained at 25C. for 2 hours and is poured onto ice and excess hydrochloric acid. The mixture is extracted with ether and the organic phase is washed with water and saturated brine, dried (Na SO and evaporated to an oil. Distillation in vacuo yields the title compound as a colorless oil.

EXAMPLE 160 Preparation of 3-triphenylmethoxy-cis-5,6methano- 1 -octyne A mixture of 13.8 g. of cis-5,6-methano-1-octyn-3-ol (Example 159) and 33.0 g. of triphcnylmethyl bromide in 100 ml. ofpyridine is heated to 100C. for 1.5 hours under an inert atmosphere. The mixture is cooled and filtered. The filtrate is partioned between ice water and ether. The organic phase is washed with cold dilute hydrochloric acid, saturated sodium bicarbonate solution. and saturated brine, dried (NaSO and evaporated to an oil. The latter is dissolved in hexane and passed to an oil. The latter is dissolved in hexane and passed through 400 g. of Florisil to yield after evaporation the title compound as a colorless oil.

EXAMPLE 161 Preparation of 1-iod0-3-triphenylmethoxy-cis-5 ,6-methano-trans- 1 octene To 160 ml. of a 0.50M solution of disiamylborane in diglyme cooled to 0C. under an inert atmosphere is added 28.6 g. (0.075 mole) 3-triphenylmethoxy-cis- 5,6-methano-1-octyne (Example 160). The mixture is allowed to come to room temperature and is stirred at ambient temperature for 3 hours. The solution is cooled to 0C, and 16.9 g. (0.225 mole) of triethylamine oxide is added portionwise such that the tempera ture is maintained at O-5C. The mixture is stirred at 0C. for 1 hour and is then poured into 300 m1. of 1 N sodium hydroxide followed immediately be a solution of 57 g. (0.225 mole) of iodine in 150 ml. of tetrahydrofuran. The mixture is stirred at ambient temperatures for 0.5 hour and poured into 1000 ml. of water. The mixture is decolorized by addition of sodium thiosulfate solution and is extracted into ether. The organic phase is washed with water and the solvent is removed in vacuo. The residue is purified by dry-column chromatography upon 1.5 kg. of alumina using hexane as eluent. The title compound is obtained as an oil.

EXAMPLES 162-168 Treatment of the carboxaldehydes listed in Table 8 below with lithium acetylide by the procedure described in Example 159 followed by treatment of the resulting 3-hydroxy-1-alkyne with triphenylmethyl bromide by the procedure of Example 160 furnishes the product 3-triphenylmethoxy-l-alkynes of the table.

TABLE 8 Ex- Starting Product 3-triphenylmeth amp carboxaldehyde oxy- 1 -alkyne 162 2-cyc1ohexenyl)- 4-( 2-cyclohexenyl )-3- acetaldehyde triphenylmethoxy-lbutyne 163 3-cyclohexeny1)- 4-(3-cyc1ohexeny1)-3- acetaldehyde triphenylmethoxy-lbutyne 164 adamantane- 1 -car- 3-( l-adamantyl )-3 triboxaldehyde phenylme thoxy- 1 -propyne 165 2-cyclohexene-car- 3-( 2-cyc1ohexenyl )-3- boxaldehyde triphenylmethoxy- 1 propyne 166 3-cyclohexene- 3-(3-cyclohcxeny1)-3- carboxaldehyde triphenylmethoxy-lpropyne 167 adamantane-2-car- 3-( 2-adamantyl )-3-triboxaldehyde phenylmethoxyl -propyne 168 (adamantyl-l )ace- 4-( 1-adamanty1)-1-butyne taldehyde C. W. Whitehead c1111.. J. Org. Chem. 26, 2814 (1961) A. H. Alberto. H. Wynhcrg and .I. Strating. Synthetic Communications. 1. 1972) EXAMPLES 169-175 Treatment of the 3-tripheny1methoxy-l-alkynes listed in Table 9 below with disiamylborane, trimethylamine oxide; iodine and aqueous sodium hydroxide by the procedure described in Example 161 furnishes the product 3-triphenylmethoxy-l-iodo-1-trans-alkenes of the table.

triphenylmethoxy-1 iodo- 1 -trans-butene EXAMPLE 176 Preparation of cyclopentylacetyl chloride To a solution of 50 g. of cyclopentaneacetic acid containing 2.9 ml. of N,N-dimethylformamide is added dropwise, with stirring, 51 g. of thionyl chloride over a period of 15 minutes. After stirring for an additional 60 minutes excess thionyl chloride is removed in vacuo and the residual oil as distilled to give 55.4 g. (94%) of product, b.p. 5758C. mm.)

EXAMPLE 177 Preparation of 1-ch1oro-4-cyc1openty1-1-trans-buten-3-one A three-necked flask filtered with a stirrer, a gas inlet tube and a gas outlet tube protected with a calcium chloride tube is surrounded by an ice-water bath. The system is flushed with acetylene for 3 minutes. Carbon tetrachloride (150 ml.) is added to the flask and acetylene is bubbled through at a fast rate for 3 minutes. A1- uminium chloride (59 g.) is added and acetylene is bubbled through the mixture for 5 minutes. The gas inlet tube is replaced by a dropping funnel protected by a calcium chloride drying tube. Cyclopentaneacetyl chloride (55.4 g., Example 176) is added to the reaction mixture with stirring over a period of about 20 minutes. The dropping funnel is replaced by the gas inlet tube and with stirring, acetylene gas is bubbled through at a rate in excess of the saturation rate. After about minutes the rate of absorption of acetylene suddenly becomes very rapid, and the acetylene is passed through as rapidly as it is absorbed. The introduction of acetylene is continued for 45 minutes after rapid absorption (which lasts about 1 hour) has subsided.

The reaction mixture is poured with stirring onto 430 g. of ice 180 ml. of saturated sodium chloride solution. The aqueous phase is extracted three times more with ether. The combined extracts are dried with anhydrous magnesium sulfate and evaporated to dryness in vacuo. After addition of 1.5 g. of hydroquinone the residual oil is distilled to give 57 g. (89%) of oil, b.p. 67-69C. (0.14 mm.).

EXAMPLE 178 Preparation of 4-cyc1openty1-1-iodo-1-trans-buten-3-one EXAMPLE 179 Preparation of 4-cyc1openty1-1-iodo-1-trans-buten-3-ol To a solution of 7.1 g. of sodium borohydride in 60 ml. of absolute alcohol, stirred in an ice bath under nitrogen atmosphere, is added dropwise, over a period of about 2 hours, a solution containing 87 g. of 4- cyclopentyl-l-iodo-trans-buten-B-one (Example 178) in 160 ml. of absolute alcohol. The temperature is 'maintained at 5-10C. The solution is poured into 850 ml. of iced water and the resulting mixture is extracted 3 times with ether. The combined extracts are washed with dilute sodium bisulfite solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 81 g. of yellow oil.

Column chromatography on a column of 1 kg. of silica gel using benzene as eluent gives g. (88%) of oily product.

Examples -199 Treatment of the listed carboxylic acids on Table 10 below with thionyl chloride by the procedure described in Example 176 followed by treatment of the resulting acid chloride with acetylene by the procedure described in Example 177, and thence by treatment of the resulting l-chloro-1-trans-a1kene-3-one with sodium iodide by the procedure described in Example 178, and then by treatment of the resulting l-iodo-l-transa1kene-3-one with sodium borohydride by the procedure described in Example 179 is productive of the product 3-hydroxy-1-iodo-l-trans-alkenes of the table.

Table 10 Ex- Starting carbox- Product 3-hydroxy-1- ample ylic acid iodo-l-trans-alkene 180 cyclohutylacetic 4-cyc1obuty1-3-hydroxyacid l-iodo- 1 -trans-butcne I81 3-cyc1opcnty1- 5-cyc1openty1-3-hypropionic acid droxy-1-iodo-1transpemene 182 4cyc1openty1- 6-cyclopenty|3'hyhutyric acid droxy-l-iodo-l-transhexenc 183 S-cyclopentyl- 7-cyc1openty1-3-hypentanoic acid droxy-l-iodo'l-transheptene 184 o-cyclopentyl- 8-cyc1opentyI-3-hyhcxanoic acid droxy- 1 -iodo- I -transocrenc 185 Z-methyl-fi-cyclo- 5 cyclopentyl-4-methylpentylpropanoic 3-hydroxy-1-iodo-I- acid trans-pentcne 186 2-cth \'1-4-cyc1oo-cyclopenty1-4-ethylpentylhutyric 3-hydroxy-14odo-1- acid trans-hcxenc 187 (Z-trans-methyl- 4-( 2-trans-methylcyc1ocyclopentyl penty1)-3 -hydroxy-1- acetic acid" iodo-l-trans-hutcne 188 cyclohcxylacetic 4-cyclohexy1-3-hydroxyacid 1 -iodo- 1 -trans-butene 189 3-cyc1ohexy1pro- S-cyclohexyl-3-hydroxypionic acid 1-iodo-1 trans-pcntcnc 190 4-cyc1ohexylfi-cyclohexy1-3-hydroxyhutyric acid" l-iodo-l-trans-hexene 191 cyc1ohcpty1ace- 4-cyc1oheptyl-3-hydroxytic acid l-iodo-Ltransbutene 192 cyclooctylacetic 4-cyc1oocty1-3-hydroxyacid 1-iodo- I -trans-butene 193 (4-methy1cyc1o- 4-(4-methy1cyc1ohexy1)- hexy1)acetic 3-hydroxy- 1 -iodo 1 acid'" trans-butene 194 (3-methy1cyclo- 4-( 3-methy1cyc1ohexyl hexy1)acetic 3-hydroxy-1-iodo-1- acid trans-butene 195 trans-2-methy1- 3-( trans-2-methy1cyc1ocyclopentane penty1)-3-hydroxy-1- carboxylic acid iodo-l-trans-propene 196 cyclohexane car- 3-cyc1ohexy1-3-hydroxyboxylic acid l-iodo-l-trans-propene 197 trans-4-methylcy- 3-( trans-4-methy1cyc1oclohexane carboxhexyl)-3-hydroxy-1- ylic acid' iodo-l-trans-propene 198 cyclooctane car- 3-cyc1ooctyl-3-hydroxyboxylic acid 1-iodo-1-rrans-propene 199 cycloheptane car- 3-cyc1ohepty1-3-hydroxyboxylic acid 1-iodo-1-trans-propene References C. G. Overherger ct al.. J. Polymer Sci.. P&A; 2. 755 (1964). 2 M. 1. Goryeav et a1.. Chem. Abs. 69, 1742. No. 186462 (1968).

"C. D. Nenitzescu and G. C. Vantu. Bull. Soc. Chim. France [5]. 2, 2209 I935).

G. Rv Yoke and R. Adams, J. Amer. Chem. Soc., 50, 1503 (1928).

5 W. Herz. J. Org. Chem., 20, 1062 (1955).

G. S. Hien and R. Adams. J. Amer. Chem. Soc., 48. 2385 (1926). 7 E. E. Royals and A. N. Neal, J. Org. Chem.v 21. 1448 (1956).

" F. F. Blicke and W. K. Johnson, J. Am. Pharm. Assoc. Sci. Ed.. 45, 443 (1956).

9 L. Ruzicka and H. A. Boekenogcn. Helv. Chim. Acta, 14, 1319 (1931 )v Table IO-Continued Table l I-Continued A. N. Burgstahlcr and I. C. Nordin. J. Amer. Chim. $00.. 83. 198N961).

J. van Braun and W. Teufferl. Ben. 58B. 2210 (I925).

M. Julia and F. LeGaffie. Bull. Soc. Chim. Fr.. 1550(I965).

'" V. N. lpatieff et al.. J. Amer. Chem. Soc.. 75. 6222(1953).

A. T. Blomquisl and F. W. Schlaet'er. J. Amer. Chem. 500.. 83. 4547 (I96l EXAMPLE 200 Preparation of 4-cyclopentyll -iodo-3-triphenylmethoxy- I -transbutene A mixture of 21.4 g. of 4-cyclopentyl-l-iodo-l-transbuten-3-ol (Example I79) in 170 ml. of dry pyridine containing 31 g. of triphenylmethyl bromide is heated on the steam-bath for 2 hours. The dark mixture is poured into 850 ml. of iced water and the resulting solution is extracted three times with ether. The combined extracts are washed with ice cold 2% hydrochloric acid until the washings are acidic, saturated sodium chloride solution. dried with anhydrous magnesium sulfate and taken to dryness. Trituration of the residue followed by filtration removes triphenylcarbinol. The mother liquor is taken to dryness and the residual syrup is chromatographed on 400 g. of florisil using hexane gives 32 g. (78%) of syrup which solidifies on standing. Recrystallization from hexane affords white crystals, m.p. 8788C.

EXAMPLE 201 Preparation of 4-cyclopentyll -iodo-3-( pmethoxyphenyldiphenyl)methoxyl trans-butene A solution of g. of 4-cyclopentyl-l-iodo-l-transbuten-3-ol (Example 179) and g. of panisylchlorodiphenylmethane in I70 ml. of dry pyridine is kept at 60C. for 18 hours, then at 70C. for 3 hours. The cooled solution is poured into 850 ml. of iced water. The resulting solution is partitioned between ether and water. The ether layer is washed with water. dried with anhydrous magnesium sulfate and taken to dryness. Further evaporation with toluene gets rid of residual pyridine. The resulting oil is chromatographed on 300 g. of florisil with hexanes to give 22.3 g. of product. The material is homogeneous according to thin layer chromatography.

EXAMPLES 202 221 Treatment of the listed 3-hydroxy-l-iodo-trans-lalkenes of Table II below with triphenylmethylbromide by the procedure described in Example 200 above is productive of the product 3-triphenylmethoxyl-iodo-trans-l-alkenes of the table.

Starting I -iodo- I trans-alkene of Example Example phenylmethoxyl -iodo- I -trans-hexene 7-cycIopentyI-3-triphenylmethoxy- I -iodo- I -trans-heptene 8-cycIopentyl-3-triphenylmethoxy- I -iodol -trans-octene 5-cyclopenyI-4-methyl- -3-triphenylmethoxy- I iodo- I -trans-pentene 6-cycIopentyI-4-ethyl- -3-triphenylmethoxyl -iodo- I -trans-hexene 4-( 2-trans-melhylcyclopentyl I-3-triphenylmethoxy- I -iodol-trans- -butene 4-cyclohexyl-3-triphenylmethoxy- I -iodo- I -trans-butene 5-cycIohexyl-3-triphenylmethoxy- I -iodo- I -rrans-pentene 6-cyclohexyI-3-triphenylmethoxy- I -iodol -trans-hexene 4-cycloheptyl-3-triphenylmethoxy- I -iodo- I -trans-butene 4-cycIooctyl-3-triphenylmethoxy- I -iodol -trans-butene 4-(4-methylcyclohexyl -3-triphcnylmethoxy- I -iodol -trans butene 4-( 3-methylcyclohexyl -3-tripheny|methoxyl -iodol -trans-butene 3-(trans-2-methylcyclopentyl I-3-triphenyI' methoxy- I -iodo-trans- -propene 3-cycIohexyl-3-triphenylmethoxy- I -iodo- I -trans-propene 3-( trans-4-methylcyclohexyl )-3-triphenyl- -methoxyl -iodo- I -trans- -propene 3-cyclooctyl-3-triphenylmethoxy- I -iodo- I -trans-propene 3-cycloheptyI-3-triphenylmethoxy- I -iodol -trans-prope ne EXAMPLE 222 Preparation of l-chloro-trans-l-octen-3-one To a slurry of 233.5 g. (1.75 moles) of aluminum chloride in 390 ml. of carbon tetrachloride, saturated with acetylene and cooled in an ice bath, is added over 20 minutes 201.9 g. 1.50 moles) of hexanoyl chloride. After the addition is complete, acetylene is bubbled into the mixture as rapidly as it is absorbed and for 1 hour after absorption becomes slow. The mixture is poured onto 1700 g. of ice and 720 ml. of saturated brine. The organic phase is separated and the aqueous phase is washed with ether. The combined organic phase and washings are washed with saturated brine, dried (Na SO.,) and evaporated. The residual oil is combined with 10 g. of hydroquinone and distilled to yield a colorless oil, b.p. 5l-52C. (0.10 torr.).

EXAMPLE 224 Preparation of 1iodo-trans-1-octen-3-one A mixture of 54.5 g. (0.364 mole) of sodium iodide and 40 g. (0.249 mole) of l-chloro-trans-1-octen-3-one (Example 222) in 360 ml. of acetone is stirred and refluxed for 24 hours. The reaction mixture is cooled, filtered and concentrated. The residue is partitioned between water and ether. The organic phase is washed with dilute sodium bicarbonate solution, brine, dried (MgSO and evaporated to an oil. This material is used directly without purification.

EXAMPLE 225 Preparation of l-iodo-trans-1-octen-3-ol A solution of 78.2 g. (0.310 moles) of l-iodo-trans-locten-3-one (Example 224) in 150 ml. of absolute ethanol is added dropwise over 2 hours to a slurry of 6.49 g. (0.172 moles) of sodium borohydride in 50 ml. of absolute ethanol cooled in an ice bath. After the addition is complete, the mixture is stirred for 2 hours with ice cooling and is then poured into 1 l. of water. The mixture is extracted into benzene and the organic phase is washed with saturated brine, dried (Na SO and evap- EXAMPLE 227 Preparation of 9-oxo-1 1a-methoxy-1S-hydroxy-l3-trans-prostenoic acid To a solution of 6.030 g. (0.01215 mole) of 1-iodo-3- triphenylmethoxy-trans-loctene (Example 128 in 8 ml. of toluene cooled to -78C. under an inert atmosphere is added 5.2 ml. of 2.34 M solution of nbutyllithium in hexane, The resulting solution is allowed to warm to 40C. and is maintained at this temperature for 1 hour. To the solution containing 3- triphenylmethoxy-trans-l-octenyllithium is then added 5.0 ml. of a 2.44 M (0.0122 mole) solution of trimethylaluminum in heptane and the mixture is allowed to warm to 10C. The mixture containing lithium trimethyl(3-triphenylmethoxytrans-1-octenyl)alanate is then cooled to 78C. and to it is added a solution of 3.94 g. (0.01215 mole) of 4-methoxy-2-(4- carbotetrahydropyran-2-y1oxyhexyl)cyclopent-2-enl-one (Example 101) dissolved in 10 ml. of diethyl ether. The mixture is allowed to warm to room temperature and is stirred at ambient temperature for 18 hours. The mixture is then poured onto ice and diluted orated. The resulting oil is dissolved into 400 ml. of ab- F and Extracted etherganic phase 18 washed with water and saturated brine, solute ethanol and treated with 5 mole percent of dried (Na SO and evaporated to yield a colorless Oil p-carboxyphenylhydrazine at 70C. for 1.5 hours to re- 2 4 The resulting crude 9-oxo-1 la-methoxy-IS- move residual ketone. The mixture is cooled and evaptrrphenylmethoxy-Sl3-trans-prosteno1c acid is (.115- orated and the residue 18 dissolved into 400 m1. of ether solved 1n 100 ml. of glacial acetic ac1d.tetrahyand 1S filtered. The filtrate 1S washed with dilute sodium O b t I d t rat d brine ,dried (Na drofuran.water (4.2.1) and is heated at 45 C. for 7 [Car (ma e so u an Sa e hours. The mixture is cooled, diluted with aqueous soa gi g 2 5 5 is fi dium chloride solution and extracted with ether. The gral e l i orislfpac sl e extract is washed with water and concentrated using P O i f e u g ga 3 5 toluene for azeotropic removal of aqueous acetic acid. 828; 6 pro uc yle S a CO or ess O1 The residue is chromatographed on silica gel to yield ton) the title product and its l5-epimer.

EXAMPLE 226 EXAMPLE 228-393 Preparation of 40 Treatment of 1rodo-3-trrphenylmethoxy (or 1'lodo'?"(p-anlsyldlphenylmethoxyHrans'loctene 3methoxy)-trans-l-alkene listed in Table 12 below A mixture of 14.92 g. (0.0588 mole) of l-iodo-transwith n-butyl lithium followed by treatment of the re p and 182 g- (00588 mOle) sulting trans-l-alkenyl lithium derivative with trimethof p-anisyldiphenylmetl yl chloride in 165 ml. oi: dry ylaluminum and then treatment of the resulting lithio y f1 15 fil 60 1 g j z t l i t f (trans-l-alkenyhgrlmethyl alanlate l witg theTbgockeczl atmosp ere. e mixture 18 COOB an t 6 SO ven 1S y-yc opent- -en mes ago ste m a e evaporated in vacuo. The residue is partiioned between below all by the procedure described in Example 227 ether and Water, and the Organic phase is washed with gives, with the exception of the l5-methoxy derivative, water and saturated brine, dried l/i s ou. angiogvapo the 1S-S-triphjenylmithgl-S-fidergvatrges correspond% rated. The residue is c romatpgrap e upon g. 0 ing to t e pro ucts o t e ta e. urt er treatment 0 Florisil packed in hexane and the product iS eluted With these intermediates with acetic acid:tetrahydrofuran:- hexane and 4:1 hexane-benzene the yield a colorelss water as described in Example 227 gives the products oil. of the table.

TABLE 12 Starting 4-oxycyclopent- Z-en- 1 -one of Starting l-iodo-ltrans alkene of Product 9-oxo-1 l-oxy- 1 5-hydroxy( methoxy 1 3 trans- Example Example Example prostenoic acid 228 101 143 9-oxo-l la-methioxy- 1 5-hydroxy-20-ethyl'1 3-transprostenoic acid 229 101 144 9-oxo-l la-methoxy-l5-hydroxy-16-ethyl-l3-transprostenoic acid 230 101 148A logo-1 loz-methoxy-lS-methoxyl 3-trans-prostenoic am 231 101 148 9-oxo-l 1a-methoxy-l5-hydroxy-l3-trans,l 7-cis-prostadienoic acid 232 101 i 152 9-oxo-1 1a-methoxy-l5-hydroxy-l6,16 dimethyl-13- I trans-prostenoic acid 233 101 1-5 6 9-oxo-1 1 a-methoxy-15-hydroxy-17.17-dimethyl-l 3- -trans-prostenoic acid 234 101 161 9-oxo-l 1a-rnethoxy l5-hydroxy-17.18-cis-methano-l3- -trans-prostenoic acid 

1. AN OPTICALLY ACITIVE COMPOUND OF THE FORMULA:
 2. The method according to claim 1 wherein the precipitated barium carbonate is separated from said ammonium salt solution and said carbonate is heated in the presence of carbon to produce barium oxide and carbon monoxide, and thereafter the barium oxide is dissolved in water to produce
 2. The compound according to claim 1 wherein R.sub.1 is methoxy, Z is hexamethylene, Y is
 3. The compound according to claim 1 wherein R.sub.1 is methoxy, Z is hexamethylene, Y is
 3. The method according to claim 1 wherein the mineral acid is phosphoric
 4. The method according to claim 1 wherein the amount of barium hydroxide is at least the stoichiometrical equivalent of said nitrile.
 4. The racemic compound according to claim 1 wherein R.sub.1 is methoxy, Z is hexamethylene, Y is
 5. The racemic compound according to claim 1 wherein R.sub.1 is methoxy, Z is hexamethylene, Y is
 6. The compound according to claim 1 wherein R.sub.1 is methoxy, Z is hexamethylene, Y is
 7. The compound according to claim 1 wherein R.sub.1 is methoxy, Z is hexamethylene, Y is
 8. The racemic compound according to claim 1 wherein R.sub.1 is methoxy, Z is hexamethylene, Y is
 9. The racemic compound according to claim 1 wherein R.sub.1 is methoxy, Z is hexamethylene, Y is
 10. The compound according to claim 1 wherein R.sub.1 is methoxy, Z is hexamethylene, Y is
 11. The compound according to claim 1 wherein R.sub.1 is methoxy, Z is hexamethylene, Y is
 12. The racemic compound according to claim 1 wherein R.sub.1 is methoxy, Z is hexamethylene, Y is
 13. The racemic compound according to claim 1 wherein R.sub.1 is methoxy, Z is hexamethylene, Y is 